Gemigliptin Inhibits Interleukin-1β–Induced Endothelial Mesenchymal Transition via Canonical-Bone Morphogenetic Protein Pathway
- Title
- Gemigliptin Inhibits Interleukin-1β–Induced Endothelial Mesenchymal Transition via Canonical-Bone Morphogenetic Protein Pathway
- Author
- 이민경
- Keywords
- LC15-0444; Dipeptidyl-peptidase IV inhibitors; Interleukin-1beta; Bone morphogenetic proteins; Endothelial-to-mesenchymal transition
- Issue Date
- 2020-06
- Publisher
- 대한내분비학회
- Citation
- Endocrinology and Metabolism, v. 35, no. 2, page. 384-395
- Abstract
- Background: Endothelial-to-mesenchymal transition (EndMT) contributes to inflammatory conditions inducing conversion of endothelial cells (ECs) into activated fibroblasts, promoting fibrotic diseases. Pro-inflammatory cytokine is the most potent inducer ofEndMT. We investigated inhibition of interleukin-1β (IL-1β)-induced EndMT by gemigliptin, a dipeptidyl peptidase-IV inhibitor.
Methods: We exposed human umbilical vein endothelial cells (HUVECs) to 10 ng/mL IL-1β/20 μM gemigliptin and analyzed theexpression of endothelial, smooth muscle, mesenchymal, and osteoblastic markers, bone morphogenetic protein (BMP), Smad, andnon-Smad signaling pathway proteins.
Results: Morphological changes showed gemigliptin blocked IL-1β-induced EndMT, upregulated EC markers, and downregulatedsmooth muscle and mesenchymal markers. IL-1β activation of HUVECs is initiated by the BMP/Smad and non-smad BMP signaling pathways. Gemigliptin inhibited IL-1β induction of BMP2 and 7, activin receptor type IA, BMP receptor type IA, and BMP receptor type II. Reversal of IL-1β-mediated inhibition of BMP-induced Smad1/5/8, Smad2, and Smad3 phosphorylation by gemigliptin suggests involvement of the Smad pathway in gemigliptin action. In the non-Smad BMP pathway, gemigliptin treatment significantly increased the deactivation of extracellular regulated protein kinase (ERK), p38, and JNK by IL-1β. Gemigliptin treatmentsuppressed BMP-2-induced expression of key osteoblastic markers including osterix, runt-related transcription factor 2, and hepcidinduring IL-1β-induced EndMT.
Conclusion: We demonstrated a novel protective mechanism of gemigliptin against fibrosis by suppressing IL-1β-induced EndMT.
- URI
- https://www.e-enm.org/journal/view.php?doi=10.3803/EnM.2020.35.2.384https://repository.hanyang.ac.kr/handle/20.500.11754/167331
- ISSN
- 2093-596X; 2093-5978
- DOI
- 10.3803/EnM.2020.35.2.384
- Appears in Collections:
- COLLEGE OF MEDICINE[S](의과대학) > MEDICINE(의학과) > Articles
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- Gemigliptin Inhibits Interleukin-1 beta-Induced Endothelial- Mesenchymal Transition via Canonical-Bone Morphogenetic Protein Pathway.pdfDownload
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